1. Field
The present disclosure relates to a biomarker for identifying a subject suitable for treatment with anti-c-Met antibodies, a method of identifying the subject including determining a level of Cbl, a mutation of Cbl, and/or a mutation of a site of c-Met for interaction with Cbl in tumor cells of the subject, and a method for inhibiting c-Met activity and/or for preventing and/or treating c-Met-related diseases, including administering an effective amount of an anti-c-Met antibody to the identified subject.
2. Description of the Related Art
c-Met is a receptor for hepatocyte growth factor (HGF), a cytokine that binds the extracellular region of the c-Met receptor tyrosine kinase to induce cell division, movement, morphogenesis, and angiogenesis of various normal cells and tumor cells. c-Met is a representative receptor tyrosine kinase existing on the surface of cells, is itself a proto-oncogene, and is sometimes involved in various mechanisms related to cancer, such as cancer development, metastasis, migration, invasion, and angiogenesis, independent from a ligand, HGF. Thus, c-Met has been recently emerging as a new target for anti-cancer therapy.
In particular, c-Met is known to be involved in induction of resistance to commonly used anti-cancer drugs, and thus is regarded as important with respect to personalized treatments. Representative anti-cancer therapeutic drugs targeting epidermal growth factor receptor EGFR (ERBB1), i.e., Eribitux or Tarceva, work by blocking the signaling related to cancer development. In addition, Herceptin, which is well known as a breast cancer therapeutic drug, targets ERBB2 (HER2) and works by blocking the transduction of signals necessary for cell proliferation. Among patients resistant to the drugs described above, the signal transduction pathway that induces cell proliferation is not blocked due to the overexpression of c-Met. Thus, c-Met has emerged as a target of interest for many pharmaceutical companies. Still, there is a need for additional anti-c-Met antibodies and related methods and compositions.
Some of the antibodies developed were found to have adverse effects. When they retain their intrinsic structures, anti-c-Met antibodies interfere with the binding of the ligand HGF to c-Met receptor, but may also act as an agonist to trigger the signaling pathway of oncogenesis by antibody-mediated dimerization of the c-Met receptor. To avoid c-Met dimerization, anti-c-Met antibodies were structurally changed from a two-armed configuration to a one-armed configuration by genetic recombination. One-armed antagonistic antibodies to c-Met were effective when used in combination with another anticancer agent, but did not exhibit significant anticancer effects when used alone.
Cbl (E3 ligase) is known to play a leading role in the degradation of c-Met. Many c-Met inhibitors initiate Cbl-mediated c-Met degradation through ubiquitination. However, c-Met inhibitors do not show the desired therapeutic effect in patients in which Cbl cannot properly interact with c-Met due to a mutation or a quantitative reduction of Cbl or due to a mutation of c-Met.
In addition, when c-Met is activated by the ligand HGF, phosphorylation at Y1003 allows the recruitment of the Cbl enzyme to c-Met. In other words, the activation of the c-Met is a prerequisite for the recruitment of the Cbl enzyme to c-Met. Accordingly, an anticancer therapy based on Cbl-mediated c-Met degradation is executed necessarily under the condition of c-Met activation which results in an adverse effect (agonism).
There is therefore a need for a novel technique by which c-Met activity may be effectively inhibited according to kind of cancer and/or a patient's genetic makeup, with a great reduction in adverse effects.